The long term objectives of this research are to understand the role of specific genes in diseases associated with aging, especially Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS). Information relevant to Parkinson disease (PD) and Huntington disease (HD) may also be obtained. Familial AD has recently been associated with genetic loci on chromosomes 19 and 21, and familial ALS with a locus on chromosome 21. A high resolution physical and genetic map of the relevant regions of these chromosomes will be developed using somatic cell hybrids and the isolation of many new polymorphic DNA probes. These will be used to refine the location of the AD and ALS genes. Physical maps consisting of overlapping contiguous DNA clones in yeast artificial chromosomes (YACs) and cosmids will be constructed for the relevant chromosomal regions. Attempts will be made to identify, isolate, and characterize the relevant genes using this information. In a complementary approach, a set of candidate genes involved in purine nucleotide metabolism and oxidative phosphorylation will be regionally mapped, converted to highly polymorphic DNA probes, and assessed for linkage to AD, ALS, HD and perhaps PD. The possible role of these biochemical pathways in these diseases will be assessed biochemically in cells from affected individuals. It is hoped that in this way the genes involved in at least the familial forms of these disorders will be identified and isolated, and that this will lead to more effective diagnosis, treatment, and prevention of these devastating diseases.